title: Chronic OVA allergen challenged TNF p55/p75 receptor deficient mice have reduced airway remodeling.
abstract: The role of tumor necrosis factor-α (TNF-α) in contributing to allergen induced airway remodeling in asthma is unknown. In this study we have utilized a mouse model of chronic OVA allergen induced airway remodeling to determine whether TNF p55/p75 receptor deficient mice (abbreviated TNF-R KO) had reduced levels of airway remodeling. Chronic OVA challenged WT mice had significantly increased levels of lung eosinophilic inflammation as well as features of airway remodeling including increased peribronchial fibrosis, thickness of the peribronchial smooth muscle layer, mucus expression, and deposition of extracellular matrix proteins. In contrast, TNF-R KO mice had significantly reduced levels of major basic protein positive peribronchial eosinophils and significantly reduced peribronchial fibrosis assessed by quantitating the area of peribronchial trichrome staining and total lung collagen. In addition, TNF-R KO mice had significantly reduced thickness of the peribronchial smooth muscle layer, area of peribronchial α-smooth muscle actin immunostaining, and levels of the extracellular matrix protein fibronectin. There was a non-significant trend for reduced mucus expression in TNF-R KO mice. Levels of peribronchial cells immunostaining positive for TGF-β1 were significantly reduced in TNF-R KO mice suggesting that reduced levels of TGF-β1 expression in TNF-R KO mice may contribute to reduced airway remodeling. Overall, this study suggests an important role for TNF-α in contributing to many features of allergen induced airway remodeling including changes in levels of peribronchial smooth muscle, subepithelial fibrosis, and deposition of extracellular matrix.
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, CA, United States. jacho@ucsd.edu
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Alexa
authors.initials: A
authors.lastname: Pham
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Taylor
authors.initials: T
authors.lastname: Doherty
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood; D015848:Interleukin-5 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010047:Ovalbumin / Q000494:pharmacology*; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053319:Tumor Necrosis Factor Decoy Receptors / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000485:Allergens; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D015848:Interleukin-5; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053773:Transforming Growth Factor beta1; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D007073:Immunoglobulin E; D010047:Ovalbumin; D003094:Collagen